The kidney has a robust capacity to finely regulate excretion of H+/OH equivalents, NaC1 and water. During metabolic alkalosis, the type B intercalated cell actively secretes HCO3 and absorbs C1- through electroneutral C1-/HCO3- exchange across the apical plasma membrane. The critical importance of this apical anion exchanger in excretion of OH equivalents during metabolic alkalosis is well known. However, the mechanism and physiological function of this CI absorption is poorly understood. Because Pds localizes to the apical membrane of the type B intercalated cell and because it transports CI- and HCO3, Pds (Sle26a4) is a candidate gene for the putative apical anion exchange process of the type B intercalated cell. Like apical anion exchange, Pds is upregulated in models of metabolic alkalosis such as with administration of aldosterone analogues (deoxycorticosterone pivalate, DOCP). In kidneys from DOCP-treated mice, pendrin expression in the apical plasma membrane increased 6-fold in type B cells. Moreover, Pds is critical in the regulation of systemic pH following administration of mineralocorticoid analogues. A surprising observation was that Pds is also critical in the generation of mineralocorticoid-induced hypertension. Under basal conditions, systolic blood pressure and body weight were similar in Pds (+/+) and Pds (-/-) mice. Following DOCP treatment weight and and hypertension were observed in Pds (+/+) mice. However, Pds (-/-) mice did not gain weight and did not develop hypertension following the administration of aldosterone analogues. These data show that C1- transport processes must be upregulated for hypertension and fluid retention to occur. How Pds modulates mineralocorticoid-induced hypertension is the subject of the present proposal. Aims of the project are to determine the following: 1) Is Pds upregulated through both aldosterone-dependent and aldosterone-independent mechanisms? 2) What is the role of the kidney in Pds-dependent, mineralocorticoid-induced fluid retention and hypertension? 3) What is the role of the cardiovascular system in Pds-dependent, mineralocorticoid-induced fluid retention and hypertension? To accomplish these objectives Pds (+/+) and Pds (-/-) mice will be studied using quantitative real time PCR, light microscopic immunohistochemistry, immunogold cytochemistry, immunoblots and CI transport studies in vitro in both perfused renal tubules and in aorta. Measurements of vascular resistance will be made in vivo and in vitro. Whole animal studies will be further employed in balance studies and measurements of GFR.